Studies Recommending Palivizumab Restriction Have Serious Deficiencies

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■■ Studies Recommending Palivizumab Restriction Have Serious Deficiencies
As an academic neonatologist who serves as the medical director of one of the largest neonatal intensive care units (NICUs) in the United States, I would like to comment on 2 recent publications 1,2 and the editorial in the January/February 2010 issue of JMCP. 3 Buckley et al. examined the outcomes associated with a prior authorization (PA) program across 3 respiratory syncytial virus (RSV) seasons (2005)(2006)(2007)(2008) in a 500,000-member health plan using claims data. The study design was retrospective and descriptive in nature. The primary endpoint was RSV-related hospitalization rates between PA and non-PA groups. In this exploratory analysis, authors concluded that PA programs can produce cost-savings to a health plan via drug cost avoidance because the rates of RSV-related hospitalization rates between the PA and non-PA group were similar.
The principle limitation of the Buckley article is that the study design is biased due to "confounding by indication." 4 Confounding by indication occurs when the treated group is sicker than the nontreated group (resulting in a selection bias) and makes treatment appear ineffective or conversely makes nontreatment look preferable. This was observed in both primary and secondary endpoints. Buckley et al. found a higher RSV-related hospitalization rate for those who received palivizumab that was marginally significant (6.4% PA-approved vs. 4.0% PA-denied, P = 0.055). 1 The authors also found a higher rate of RSV-related emergency department (ED) visits in the PA-approved group (2.2%) compared to the PA-denied group (1.4%, P = 0.019).
Obviously, the patients who received PA would include those who had risk factors and would be expected to have more ED visits, as well as hospitalizations. The PA approval group had a lower gestational age and greater variance in their gestational age than the infants that were denied palivizumab (mean gestational age 32.5 weeks [SD of 4] vs. 34.4 weeks [SD of 2.5], P < 0.001). Consequently, it is not a valid assumption that the medical management of these 2 cohorts (PA-approved vs. PA-denied) is similar. Multivariate analysis would need to be conducted to control for these various characteristics.
Also, using only RSV-specific International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes most likely underestimate the actual rates of RSV in real world settings. The use of bronchiolitis, pneumonia, and unspecified bronchiolitis codes may increase the number of potential RSV cases as RSV is the etiologic agent for approximately 50%-80% of winter bronchiolitis cases. 5 Furthermore, the American Academy of Pediatrics (AAP) guidelines for bronchiolitis do not recommend routine lab testing because the diagnosis of RSV does not alter management of these patients. 6 Therefore, lab tests are not routinely performed in clinical practice. It is not a surprise that rates of RSV were lower than those observed in clinical trials.
Compliance patterns of palivizumab were not examined in this publication. Palivizumab involves monthly injections prior and throughout the RSV season, 7 typically defined as November to March. Because compliance with palivizumab use was not observed, this may markedly affect the rates of RSV hospitalization and extracorporeal membrane oxygenation (ECMO) utilization.
The study did not include health care costs beyond the acute RSV episode.  8 The study was improperly designed to determine the appropriateness of their PA process. Based on the limited information provided and the biases mentioned above, it is unclear if the PA program saved 2.4 million dollars over 3 years. The PA program still showed a significant RSV hospitalization rate of 4.0% (35%-40% of all hospitalizations observed in the study). 1 This suggests that Select Health's policy for prophylaxis did not capture all infants at high risk for severe RSV disease.
The publication entitled "Medical Utilization Associated with Palivizumab Compliance in a Commercial and Managed Medicaid Health Plan" by Diehl et al. warrants comments. 2 The authors examined cost and outcomes among patients who were prescribed and received palivizumab according to the dosing schedule based on AAP guidelines from 2006 to those who did not receive palvizumab in a managed care plan of approximately 400,000 members. The study included only those who were approved for palivizumab during the 2006-2007 RSV season and examined a small sample of compliant versus noncompliant infants (N = 245). The authors did not find a significant relationship between palivizumab compliance and health care costs, raising the question whether full dosing of RSV prophylaxis is necessary.
The study was descriptive in nature and was not properly designed to make any associations between compliance and outcomes. Limited by a relatively small sample size, perhaps differences between groups were not recognized.
The study did not adequately control for observed and unobserved confounding between the 2 groups of interest (compliant and noncompliant infants). Confounding by indication exists in the study as RSV-related outpatient rates were higher in compliant patients vs. noncompliant patients (9.6% vs. 5.8%). mittee as attentive to a perspective of "high cost of prophylaxis and inconsistency in identification of high risk groups." 3 However, there is no clinical evidence to support abbreviated dosing. Other recent articles were published in Pediatrics which provide different perspectives of the guidelines. 12,13 In the face of health care constraints, PA for the use of monoclonal antibody as immunotherapy for RSV is not surprising. Arbitrary decisions by health care organizations place the clinician in an ethical conundrum of doing "what is right for the patient." Are we, the clinicians, putting 145,000 additional infants at risk of severe RSV disease by following the 2009 AAP Guidelines for the use of palivizumab? Are we increasing their risk of recurrent reactive airway disease later in life? Clinicians want to do the "best" for their patients based on solid evidence-based medicine.
There was a significant difference in patient follow-up. Patients in the noncompliant group had a longer follow-up (i.e., births may have been closer to the start of the RSV season compared to the end of the RSV season). This may have impacted the cost comparisons (i.e., costs for the compliant group were less because of the short follow-up time) if the results were not standardized.
The authors made false assumptions regarding adherence/ compliance in this publication. By assuming that "members born during the RSV season were assumed to receive their first dose as an inpatient", this skews the conclusions. Based on data from the Synagis Outcomes Registry, only 43% of discharges from a NICU received the first palivizumab dose while still in the hospital; the other 57% of NICU dose candidates received their first palivizumab dose in the outpatient setting after hospital discharge during the 2003-2004 season. 9 The conclusion of this registry analysis suggests that there may be a significant gap in the recommended dosing of palivizumab immunoprophylaxis in NICU patients, and that timing of the dose is critical for these infants during the transition period from inpatient to outpatient setting during the RSV season. The assumption by Diehl regarding the receipt of first dose can lead to misclassification of infants and result in a null comparison of outcomes.
There was also imprecise measure for non-normal cost (median). Cost data are often skewed data and do not necessarily follow a normal distribution. Typically, mean and standard deviation are reported along with the median. Authors reported median costs to point out no difference in health care costs between groups, whereas mean costs suggest an increased cost trend for noncompliant patients. In some cases, cost data are adjusted in a generalized linear model, but this was not performed in this study.
The authors suggest that utilization management may be the key to cost-effective treatment. However, the study itself was regarding compliance, which is a separate concept from utilization management and the link between the 2 cannot automatically be made.
Finally, I would like to make a few comments on the editorial in the same issue of JMCP. 3 It has been stated that "palivizumab product labelling involves dosing and regimen completion rates that are implausible in the real world." However, Frogel et al. (2010) reports compliance rates as high as 80%-99.5% (Tables  1 and 2), although definitions of compliance varies among studies. 10 The study by Frogel et al. was useful to discuss various interventions that were shown to improve compliance rates, which also were not highlighted in the editorial. On the other end of the spectrum, a reported 30% compliance rate during the 2006-2007 RSV season reported by Diehl et al. is alarming-reasons for the low rate or ways to improve compliance was not fully discussed. 2 The editorial viewed the 2009 AAP guidelines 11 and com-

International Classification of Disease, Ninth Revision, Clinical
Modification (ICD-9-CM) codes. This method was used to focus on only documented RSV disease. Incorporating nonspecific codes for bronchiolitis, pneumonia, and unspecified bronchiolitis codes would have the potential to overestimate the incidence of documented RSV disease and associated hospitalizations, emergency room (ER) visits, and overall costs. Certainly palivizumab has not been shown to prevent bronchiolitis secondary to other viruses (influenza, parainfluenza, metapneumovirus, bocavirus, adenovirus, and possibly rhinovirus). Our integrated health system has embraced viral testing both for limiting unnecessary antibiotic use and for cohorting. As a health care system, 68.2% of all children presenting with respiratory symptoms with a subsequent hospital admission underwent viral testing which includes RSV for the 2005-2008 study period.
Compliance was not a pre-defined endpoint of our study and was not assessed for the PA-approved group that went on to receive at least 1 dose of palivizumab. However, this study still provides real-world palivizumab utilization patterns for a 500,000-member health plan.
Ours is the first published study to determine rates of hospitalizations, ER visits, and drug cost avoidance associated with the application of PA criteria for coverage determination of palivizumab. We acknowledge the limitations inherent in using administrative claims data. However, claims data accurately reflect hospitalizations, ER visits, and medication costs, all of which were study endpoints. Our study provides a foundation for the conduct of research by others to further inform about resource utilization and identification of the high-risk groups most likely to benefit from prophylaxis of severe RSV.

DISCLOSURES
The authors report no conflicts of interest related to the subjects or products discussed in this response.

The Authors Respond:
We think that Stewart has missed the point of our study. We did not set out to determine the efficacy of palivizumab in prophylaxis for respiratory syncytial virus (RSV) as measured by resource utilization. Rather, the objective was to analyze the outcomes of a prior authorization (PA) program designed to reduce inappropriate RSV prophylaxis with palivizumab by requiring the use of this drug in accordance with guidelines from the American Academy of Pediatrics (AAP). 1 Because prophylaxis with palivizumab is widely accepted as the standard of care to prevent serious RSV disease in high-risk infants, it would not be acceptable to conduct a study that would deny this population coverage of prophylactic therapy. In our study population, there were no babies denied access to palivizumab who met the AAP criteria for risk.
Our PA process was directed at inappropriate use of palivizumab in babies who did not meet AAP criteria. The infants included in the PA-approved and PA-denied groups did not undergo a randomization process for the variable of interest. As a result, hidden confounding elements may impact the outcomes in unpredictable ways. Multivariate analysis would not be able to control for all risk factors defined by the 2006 AAP guidelines based solely on medical and pharmacy claims data. Currently, there are still inconsistencies that exist among studies that attempt to define risk factors identifying children at greatest risk of serious RSV lower respiratory tract disease. Additionally, all PAs are initiated by the infant's health care provider. Regardless of the infant's fulfillment of the health plan's PA criteria, one could assume that the requesting provider considered the infant was at some level of increased risk of severe RSV disease.
In the design of this study we chose only the RSV-specific

The Editors Respond:
Stewart predictably advocates for unrestricted use of palivizumab in response to our publication of 2 articles that described evaluation of clinical and cost outcomes associated with quality improvement initiatives in 2 unrelated managed care organizations. It is worth noting that the utilization management program described by Buckley et al. 1 was developed in a health system that is celebrated for its commitment to continuous quality improvement 2 and has been ranked consistently in the top 5 integrated health systems each year for the last decade. 3 Second, this utilization management program was based on the best evidence as evaluated by infectious disease experts writing for the American Academy of Pediatrics (AAP) in 2006 4 and was developed by clinicians in this integrated health system who have a focus on quality improvement including the elimination of waste. The results of evaluation of this intervention involving a prior authorization (PA) requirement for coverage of palivizumab include palivizumab drug cost savings of more than $2.4 million over 3 years without evidence of adverse clinical outcomes. Although preliminary because of its exploratory and descriptive design, this study by Buckley et al. is good news for health plans, including the 85 health plans that ranked prevention of respiratory syncytial virus (RSV) infection as the fourth highest-priority therapy category for utilization management of specialty pharmaceuticals in 2009, and the 10% of these health plans that reported "recently" adding a PA for palivizumab for RSV in 2009. 5 Stewart complains of "confounding by indication." We agree that the treated group in Buckley et al. met the PA criteria based on the AAP guideline. Therefore, the treated group

The Authors Respond:
In response to our study, 1 Stewart describes several methodological limitations that are inherent in retrospective study designs. Although many of these limitations were addressed in our original article, some warrant further discussion. Stewart is concerned that our relatively small sample size could possibly lead to a Type II error. Although it would have been feasible to increase our sample size by including multiple respiratory syncytial virus (RSV) seasons, we chose to limit our study to 1 RSV season due to subsequent changes in the American Academy of Pediatrics (AAP) guidelines for palivizumab 2 as well as our health plan's prior authorization policy. Accordingly, the compliance patterns observed in our cohort correspond to the specific policies in place during the RSV season under study.
Stewart made errors in his interpretation of our data. As Stewart points out, the retrospective nature of administrative claims data does inherently limit the ability to control for treatment indication. Nonetheless, the difference in RSV-related outpatient visits highlighted by Stewart was not found to be statistically significant between the 2 groups. Stewart also points out the differences in length of patient follow-up as a potential influence on cost data. Because we reported all cost data on a per member per month (PMPM) basis, the differences in length of membership were thereby controlled.
Additionally, our assumption that the first dose of palivizumab was given in the neonatal intensive care unit (NICU) was appropriate and necessary as part of conducting research with administrative claims data. As a health plan we often do not have access to medical claims until months after the date of service. And, we do not have the claim level detail on inpatient visits to know whether or not a specific dose of a specific medication was given. As a result, compliance for our study could take into consideration only outpatient doses.
Finally, our comments questioning the cost-effectiveness of palivizumab prophylaxis were based on the finding that compliant infants continued to have RSV-related outpatient visits. We feel that this is an important issue that warrants further investigation considering the need to control rising costs in today's health care environment. Only by raising these issues and performing the appropriate studies can we properly develop the strategies, such as prior authorization, utilized by managed care organizations to identify the most appropriate patient populations for high-cost drugs.
Despite the criticism from Stewart of the report by Buckley et al. and of the report by Diehl et al. regarding outcomes associated with compliance versus noncompliance with palivizumab dosing, 10 these 2 reports include findings that comport with those of previous research. As we noted in our assessment of the available evidence on the subject, data regarding the relationship between palivizumab compliance and outcomes in routine clinical practice are mixed. 11 In the Palivizumab Outcomes Registry study, investigators found no significant association between RSV-related hospitalization and compliance defined as receipt of the number of expected palivizumab injections regardless of timing; however, when compliance was defined as the receipt of each dose within 35 days of the previous dose in patients with at least 2 doses, the compliant group had a 0.5% lower rate of RSV-related hospitalization (1.2% vs. 1.7%, P =0.007). 9 By this measure, "moving the needle" from noncompliance to compliance in 200 palivizumab-treated infants would prevent 1 RSV-related hospitalization. Using a more stringent definition of compliance and a small sample limited to infants meeting the health plan's PA criteria, Diehl et al. found a 1.2% rate of RSV-related hospitalization among at-risk infants who received palivizumab but were noncompliant. 10 Given the mixed and limited evidence available to date, the high cost of palivizumab, and the potentially serious consequences of noncompliance for at-risk infants, we hope that future research will examine more closely the association of the timing of palivizumab dosing with rates and costs of RSV hospitalizations and other negative clinical outcomes (e.g., use of intensive care units or ventilators). These analyses are relatively simple to perform using administrative claims data, and we encourage health plans to do so.
In summary, we observe that (a) the PA-denied group in Buckley et al. did not meet best evidence criteria for use of palivizumab; (b) RSV hospitalizations occurred in the clinical trials and in the Palivizumab Outcomes Registry among patients who received palivizumab prophylaxis; (c) the cumulative data suggest that there is a small but clinically important difference in RSV hospitalization for patients compliant with palvizumab dosing versus those noncompliant; and (d) health plans are expected to endorse and promote evidence-based practice. We defer to the infectious disease experts and the AAP 2009 policy statement for unequivocal answers to Stewart's other criticisms of the use of evidence in clinical practice.
should be sicker, and we note that the PA process was intended to produce that very outcome (i.e., target palivizumab therapy to children most likely to benefit from it). Buckley et al. also pointed out in their study report that the PA-denied group was healthier. The assertion of confounding by indication, although theoretically correct in any observational comparison of treatment approaches, is a red herring in this instance. Buckley et al. did not study the efficacy of palivizumab (i.e., treatment versus nontreatment) in at-risk infants; clinical trials have already shown that palivizumab is efficacious in this group. Instead, Buckley et al. described the outcomes of a PA process that targeted the use of palivizumab to at-risk infants (as opposed to infants who did not meet the AAP criteria for risk). Importantly, the developers of this clinically sound PA intervention did not advocate nontreatment of at-risk infants; they advocated targeting treatment to only at-risk infants.
Stewart also criticizes the study report by Buckley et al. as "improperly designed to determine the appropriateness of the PA process," which apparently represents criticism of the AAP and its infectious disease experts who created the policy statement and recommendations for the use of palivizumab for the prevention of RSV infections. 4 These infectious disease experts were apparently mindful of the high cost of palivizumab and the inconsistency in the medical literature regarding the factors that reliably predict risk of RSV-related hospitalization, because the 2009 update was more definitive than the previous AAP guidance (2006) in specifying the groups of infants who are not likely to benefit from immunoprophylaxis with palivizumab. 6 Stewart cites the RSV hospitalization rate of 4.0% for the PA-denied group in Buckley et al. as evidence of lack of costeffectiveness for the PA process, apparently suggesting that some or all of the hospitalizations in the PA-denied group could have been prevented had physicians in this health plan's network been given "free rein" to prescribe palivizumab regardless of AAP criteria. This is speculation because no study has assessed the efficacy of palivizumab in infants not at high risk. However, the speculation appears to be partially contravened by evidence of RSV hospitalization rates in palivizumabtreated patients: 4.8% in the IMpact-RSV clinical trial 7 that was the basis for U.S. Food and Drug Administration (FDA) approval of palivizumab for the prevention of serious lower respiratory tract disease caused by RSV in pediatric patients at high risk of RSV disease; 8 6.4% in the PA-approved group in Buckley et al.'s study; and 1.3% in the Palivizumab Outcomes Registry study, a prospective observational study of palivizumab-treated patients in routine clinical practice. 9 The range of RSV hospitalization rates is notably wide. As Buckley et al. suggested in their study report, making comparisons to previous work is difficult because of differences among studies. The Registry study was not limited to infants meeting AAP criteria and defined RSV hospitalizations as stays of 24 hours or more in which "RSV infection was confirmed by virology testing." 9